Tannic Acid as a Natural Ferroptosis Inhibitor: Mechanisms and Beneficial Role of 3’‐ O ‐Galloylation

Abstract Ferroptosis is a recently reported cellular apoptosis form. Screening for safe ferroptosis inhibitors and elucidation of the mechanisms have recently attracted significant attention. In this study, the ferroptosis‐inhibitory activities of gallotannin tannic acid and its parent, 1,2,3,4,6‐penta‐ O ‐galloyl‐ β ‐D‐glucopyranose ( β ‐PGG), were comparatively evaluated using an erastin‐mediated bone marrow‐derived mesenchymal stem cell (bmMSC) model, employing ferrostatin‐1 (Fer‐1) as a positive control. The relative inhibitory levels decreased in the following order: Fer‐1>tannic acid> β ‐PGG. In the radical‐trapping assays, the relative levels decreased in the order of tannic acid> β ‐PGG >Fer‐1. When mixed with ferrous ions, the UV‐visible spectra of tannic acid, β ‐PGG, and Fer‐1 changed. In conclusion, natural tannic acid could undergo radical trapping and ferrous complexation pathways to inhibit ferroptosis in the bmMSCs. In contrast to Fer‐1, which utilized ferrous complexation to initiate its catalytic recycle, tannic acid mediated ferrous complexation to indirectly trap the radicals. The 3’‐ O ‐galloylation reaction enhanced the radical trapping and indirect radical trapping of tannic acid to enhance ferroptosis inhibition.